Article

Extended Follow-up Analysis of First-Line Treatment for Metastatic Gastric Cancer, Gastroesophageal Junction Cancer and Esophageal Adenocarcinoma

Author(s):

Sponsored by Bristol Myers Squibb

Certain metastatic gastroesophageal cancers, such as gastric cancer (GC), gastroesophageal junction cancer (GEJC) and esophageal adenocarcinoma (EAC), have been associated with challenging prognoses and poor survival rates.1,2,3 The five-year survival rates for people in the United States with metastatic gastric and esophageal cancers from 2012 to 2018 were approximately 5.9% and 5.7%, respectively. 4,5 Combined, gastric and esophageal cancers account for approximately 4.5% of all cancer deaths in the U.S.4,5 Therefore, there is a need for treatment advances and options that may offer hope and the chance for a longer life.

In recent years, one area of research in this setting has focused on immunotherapy-based treatment options. This led to the 2021 U.S. Food and Drug Administration (FDA) approval of Opdivo® (nivolumab) (injection for intravenous use), in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the treatment of adult patients with advanced or metastatic GC, GEJC, and EAC, regardless of PD-L1 expression status.6

Lee James, MD, PhD

Lee James, MD, PhD

“This approval represented important progress in metastatic gastroesophageal cancer, providing an option to patients who have historically experienced high unmet need,” said Lee James, MD, PhD, vice president of U.S. Medical Oncology at Bristol Myers Squibb. “Ongoing research in this space continues to be critical, with the aim of expanding our understanding of the role of immunotherapy-based approaches in this treatment landscape.”

The approval of the Opdivo-based combination in this setting was supported by one-year results from CheckMate -649, a Phase 3 clinical trial. Follow-up three-year data were presented at the ASCO Gastrointestinal Cancers Symposium in January 2023, which analyzed long-term survival in patients regardless of PD-L1 expression status versus chemotherapy alone.

Opdivo is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis and renal dysfunction, dermatologic adverse reactions, other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when Opdivo is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.6 Please see the Important Safety Information section below.

Data from CheckMate -649 Demonstrated Superior Overall Survival (OS) in Patients Regardless of PD-L1 Status at One Year

The CheckMate -649 clinical trial evaluated Opdivo in combination with mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin), compared with chemotherapy (mFOLFOX6 or CapeOX) alone, in patients with previously untreated advanced or metastatic GC, GEJC, and EAC.6 The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2) positive, or had untreated central nervous system (CNS) metastases.6

The primary endpoints assessed in patients with PD-L1 combined positive score (CPS) ≥5 were overall survival (OS) and progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR).6 At the primary analysis (minimum follow-up 12.1 months), median OS was 14.4 months (95% Confidence Interval [CI]: 13.1-16.2) with Opdivo plus chemotherapy versus 11.1 months (95% CI: 10.0-12.1) with chemotherapy alone (Hazard Ratio [HR] 0.71; 95% CI: 0.61-0.83; P<0.0001).6 Median PFS was 7.7 months (95% CI: 7.0-9.2) in the Opdivo plus chemotherapy arm versus 6.0 months (95% CI: 5.6-6.9) with chemotherapy alone (HR 0.68; 95% CI: 0.58-0.79; P<0.0001).6

Secondary endpoints at the primary analysis included OS in patients with PD-L1 CPS ≥1 and in all randomized patients. Opdivo plus chemotherapy demonstrated superior OS compared with chemotherapy alone in both patient populations.6 Median OS was 14.0 months (95% CI: 12.6-15.0) with Opdivo plus chemotherapy versus 11.3 months (95% CI: 10.6-12.3) with chemotherapy alone (HR 0.77; 95% CI: 0.68-0.88; P<0.0001) in patients with PD-L1 CPS ≥1.6 In all randomized patients, median OS was 13.8 months (95% CI: 12.6-14.6) with Opdivo plus chemotherapy versus 11.6 months (95% CI: 10.9-12.5) with chemotherapy alone (HR 0.80; 95% CI: 0.71-0.90; P=0.0002).6

At the primary analysis in all randomized patients, 55% of patients on Opdivo in combination with chemotherapy were alive at one year versus 48% of patients on chemotherapy alone.7 The OS rates were not pre-specified within the study protocol and were not powered to detect differences between treatment arms.6

Opdivo (nivolumab) and/or chemotherapy were discontinued in 44% of patients and at least one dose was withheld in 76% of patients due to an adverse reaction.6 Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with Opdivo in combination with chemotherapy.6 These included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation.6 Serious adverse reactions occurred in 52% of patients treated with Opdivo in combination with chemotherapy.6 The most frequent serious adverse reactions reported in ≥2% of patients treated with Opdivo in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). The most common adverse reactions reported in ≥20% of patients treated with Opdivo in combination with chemotherapy were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).6

Data from Extended Three-Year Follow-up of CheckMate -649 Analyzed Long-Term Survival Versus Chemotherapy Alone in Patients Regardless of PD-L1 Status

In the extended follow-up analysis (36.2 months minimum follow-up) in patients with PD-L1 CPS ≥5, median OS was 14.4 months (95% CI: 13.1-16.2) with Opdivo plus chemotherapy versus 11.1 months (95% CI: 10.0-12.1) with chemotherapy alone (HR 0.70; 95% CI: 0.61-0.81) (see Figure 1 below).8 Median PFS was 8.3 months (95% CI: 7.0-9.3) in the Opdivo plus chemotherapy arm versus 6.1 months (95% CI: 5.6-6.9) with chemotherapy alone (HR 0.70; 95% CI: 0.60-0.81).8

Figure 1

The exploratory 36-month analysis was not statistically powered to detect differences between treatment arms.

In the extended follow-up analysis (36.2 months minimum follow-up) in patients with PD-L1 CPS ≥1, median OS was 13.8 months (95% CI: 12.4-14.8) with Opdivo plus chemotherapy versus 11.3 months (95% CI: 10.7-12.3) with chemotherapy alone (HR 0.76; 95% CI: 0.67-0.86) (see Figure 2 below).9

Figure 2

In all randomized patients, median OS was 13.7 months (95% CI: 12.4-14.5) with Opdivo plus chemotherapy versus 11.6 months (95% CI: 10.9-12.5) with chemotherapy alone (HR 0.79; 95% CI: 0.71-0.88) (see Figure 3 below).8

Figure 3

Please see additional Important Safety Information below.

Opdivo was FDA-approved in 2021 as the first and only approved immunotherapy combined with chemotherapy (please see below for full indication statement) to deliver superior OS compared with chemotherapy alone across first-line metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma based on the CheckMate -649 trial of these patients. It is currently the only first-line immunotherapy-based regimen approved in patients with gastric cancer regardless of PD-L1 expression, including patients with HER2- negative status.

“With these latest findings we see the potential for long term survival with Opdivo plus chemotherapy compared with chemotherapy alone over three years for certain patients, as we add to the available data for this treatment approach as an important option for certain metastatic gastroesophageal cancers,” said Dr. Lee James. “This is representative of our ongoing and deep commitment to patients facing these diagnoses and their loved ones, as well as the healthcare professionals caring for them – as we collectively hope for treatment options that may offer the chance at a longer life.”

For more information about Opdivo, please visit www.Opdivo.com.

INDICATION

OPDIVO® (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune- mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO. Early identification and management are essential to ensure safe use of OPDIVO. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment with OPDIVO. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%).

Immune-Mediated Colitis

OPDIVO can cause immune-mediated colitis. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid- refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%).

Immune-Mediated Endocrinopathies

OPDIVO can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune- mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

Withhold or permanently discontinue OPDIVO depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%).

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or were reported with the use of other PD- 1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving OPDIVO, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO can cause severe infusion-related reactions. Discontinue OPDIVO in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate -649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation.

Common Adverse Reactions

In Checkmate -649, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%).

Please see US Full Prescribing Information for OPDIVO.

References

  1. Yang D, Hendifar A, Lenz C, et al. Survival of Metastatic Gastric Cancer: Significance of Age, Sex and Race/Ethnicity. J Gastrointest Oncol. 2011;2(2):77-84. doi:10.3978/j.issn.2078-6891.2010.025
  2. Wang K, Johnson A, Ali SM, et al. Comprehensive Genomic Profiling of Advanced Esophageal Squamous Cell Carcinomas and Esophageal Adenocarcinomas Reveals Similarities and Differences. Oncologist. 2015;20(10):1132-1139. doi:10.1634/theoncologist.2015-0156
  3. Lin D, Khan U, Goetze TO, et al. Gastroesophageal Junction Adenocarcinoma: Is There an Optimal Management? Am Soc Clin Oncol Educ Book. 2019;39:e88-e95. doi:10.1200/EDBK_236827
  4. National Cancer Institute. Cancer Stat Facts: Stomach Cancer. Surveillance, Epidemiology, and End Results Program (SEER). Accessed February 2023. https://seer.cancer.gov/statfacts/html/stomach.html.
  5. National Cancer Institute. Cancer Stat Facts: Esophageal Cancer. Surveillance, Epidemiology, and End Results Program (SEER). Accessed January 2023. https://seer.cancer.gov/statfacts/html/esoph.html.
  6. Opdivo Prescribing Information. Opdivo US Product Information. Last Updated: May 2022. Princeton, NJ: Bristol Myers Squibb Company.
  7. Moehler M, Shitara K, Garrido M, et al. Nivolumab Plus Chemotherapy versus Chemotherapy as First-line Treatment for Advanced Gastric Cancer/Gastroesophageal Junction Cancer/Esophageal Adenocarcinoma: Ffirst Rresults of the CheckMate 649 study. Late-breaker Presented at 2020 European Society for Medical Oncology (ESMO) Virtual Congress. September 19-21, 2020.
  8. Janjigian Y, Shitara K, Moehler M, et al. Nivolumab (NIVO) Plus Chemotherapy (chemo) vs Chemo as First-line (1L) Treatment for Advanced Gastric Cancer/Gastroesophageal Junction Cancer/Esophageal Adenocarcinoma (GC/GEJC/EAC): 3-year Follow-up from CheckMate 649. Oral presentation at 2023 ASCO GI Cancers Symposium. January 19-21, 2023.
  9. Data on File. Bristol Myers Squibb Company; 2022.

© 2023 Bristol-Myers Squibb Company.

OPDIVO® and the related logos are registered trademarks of Bristol-Myers Squibb Company.

1506-US-2300043 04/23